In the therapy of neurological diseases, namely disorders in the central nervous system and the peripheral nervous system, therapeutic agents for the central nervous system have been vigorously studied and applied. In contrast, very few therapeutic agents for diseases of the peripheral nervous system, especially disorders of peripheral nerves, have been put to practical use worldwide.
Japanese Laid-Open Patent Publication No. 34912/1977 discloses a pharmaceutical comprising a dispersion or solution of ganglioside in a medium, which is effective for pathology attributed to neural stimulus transmission disorders in the central nervous system and the peripheral nervous system. Only ganglioside (a product named Cronassial is sold in Italy), a natural carbohydrate, disclosed in the above-cited laid-open publication and mecobalamin, a kind of vitamin, have so far been applied clinically to diseases of the peripheral nervous system, but no entirely satisfactory effect has been obtained.
Japanese Patent Publication No. 28548/1984 discloses 2-isopropylaminopyrimidine ortho-phosphate represented by the following formula ##STR2## and a therapeutic agent comprising this compound for treatment of peripheral nerve diseases. As far as the present inventors know, the above compound (common name, isaxonine phosphate to be abbreviated hereinafter as isaxonine) is the first synthetic compound which was used in clinical research on peripheral nerve disorders (La Nouvelle Presse Medicale, vol. 16, pages 1189-1280, 1982). It appears that this compound is not actually marketed now. No synthetic compound has been known which is used for treating peripheral nerve disorders.
Factors acting on the growth and regeneration of nerves are known to exist in an animal. They are called a nerve growth factor (NGF) or a neurotrophic factor. These factors are high-molecular proteins, and many problems exist which have to be technically solved in applying them to neurological diseases.
Japanese Laid-Open Patent Publication No. 222424/1984 discloses that a gangliside mixture extracted from the cow brain or a single component in gangliosides acts promotingly on the proliferation of the primary culture of nerve cells or neuroblastoma cells, and the formation and growth of the neurite, and that it has the same effect as mecobalamin in an animal model of neurological disorder. Furthermore, as stated above, ganglioside is actually used clinically for the treatment of disorders in the peripheral nervous system and the central nervous system (not psychopathy).
Ganglioside, however, is a natural extract originated from an animal of a different species, and the antigenicity of itself or a foreign material contained in it becomes a problem. Another problem is that it is very difficult to specify and define it as a uniform stable substance in drug preparation.
Japanese Laid-Open Patent Publication No. 144,765/1984 discloses a 2-(1-piperazinyl)pyrimidine having the following formula (I) ##STR3## wherein one of P and Q represents hydrogen or a hydroxyl or lower alkyl group and the other represents hydrogen, and X represents a group of the formula CO--R.sub.1 in which R.sub.1 is a lower alkyl group, a group of the formula ##STR4## in which R.sub.2 is hydrogen or a lower alkyl, phenyl, p-hydroxyphenyl, benzyl, p-hydroxybenzyl, hydroxymethyl, 1-hydroxyethyl or 3-indolylmethyl group, R.sub.3 is hydrogen, a lower alkylcarbonyl group, a benzoyl group, an acyl group derived from an amino acid selected from glycine, phenylglycine, alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, serine, threonine and tryptophan, or an acyl group derived from a dipeptide comprised of two of the above amino acids, or R.sub.2 and R.sub.3 together may form an ethylene group, a group of the formula Alk--COOY in which Alk represents a liner or branched alkylene group having 1 to 4 carbon atoms and Y represents hydrogen or a lower alkyl group, a group of the formula Alk--CH.sub.2 OZ in which Alk is as defined, and Z represents hydrogen or a lower alkyl, (lower alkoxy)-lower alkyl, or lower alkylcarbonyl group, or a group of the formula Alk--CO--W in which Alk is as defined and W represents a lower alkyl group or its pharmaceutically acceptable acid addition salts. This patent document states that the compounds of formula (I) or acid addition salts thereof have dopamine-type psychotherapeutic activity.
Japanese Laid-Open Patent Publication No. 144,766/1984 describes an acid addition salt of 2-(1-piperazinyl)pyrimidine with a dicarboxylic acid, and states that this compound has good phrenotropic activity having dopamine mechanism, particularly antipsychotic activity, antimelanchoric activity and ataractic and tranguilizing activity.
Japanese Laid-Open Patent Publication No. 155,316/1984 discloses a drug having dopamine-acting phrenotropic activity comprising as an active ingredient a 2-piperazinopyrimidine represented by the formula ##STR5## wherein R.sup.1 represents hydrogen or a hydroxyl group, and R.sup.2 represents hydrogen or an alkyl group having 1 to 6 carbon atoms, or a pharmacologically acceptable acid addition salt thereof.
International Laid-Open WO85/00168 discloses 2-(1-piperazinyl)pyrimidine 2-naphthalenesulfonate represented by the following formula ##STR6## and states that this compound has dopamine phrenotropic activity.
However, none of the above four cited patent documents describe or suggest that 2-piperazinopyrimidines are effective for reproducing neurocytes and can be applied to peripheral nerve disorders, and central nerve disorders which are not psychopathy.
It is an object of this invention therefore to provide a novel therapeutic agent for neurological diseases.
Another object of this invention provides a novel therapeutic agent for neurological diseases effective for reproducing and repairing neurocytes.
Still another object of this invention is to provide a novel therapeutic agent for neurological diseases which can be applied to disorders of peripheral nerves.
Yet another object of this invention is to provide a novel therapeutic agent for neurological disorders which can be applied to central nerve disorders that are regarded as being primarily due to the involvement of derangement of the active and metabolic systems of nerve transmitting substances.
Further objects of this invention along with its advantages will become apparent from the following description.
According to this invention, the above objects and advantages of this invention are achieved by a therapeutic agent for neurological diseases, comprising as an active ingredient a pyrimidine represented by the following formula (I) ##STR7## wherein
R.sup.1 represents a hydrogen atom, an acyl group having 2 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonylmethyl group having 3 to 5 carbon atoms, a 3,4-dimethoxybenzoyl group or a 3,4-methylenedioxybenzyl group,
R.sup.2 represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 5 carbon atoms or an alkoxycarbonyl group having 2 to 4 carbon atoms,
R.sup.3 represents a hydrogen atom, an alkoxycarbonyl group having 2 to 4 carbon atoms, a dialkylaminocarbonyl group having 1 to 9 carbon atoms in each alkyl moiety, an alkoxy group having 1 to 5 carbon atoms, or a hydroxyethyl group,
R.sup.2 and R.sup.3, together with the carbon atoms to which they are bonded, may form a 5- to 7-membered carbocyclic ring or a heterocyclic ring having N, O or S as the hetero atom, and
R.sup.4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkylthio group having 1 to 4 carbon atoms;
or a pharmaceutically acceptable salt thereof.
In formula (I), R.sup.1 represents a hydrogen atom, an acyl group having 2 to 4 carbon atoms, an alkoxycarbonyl group having 2 to 5 carbon atoms, an alkoxycarbonylmethyl group having 3 to 5 carbon atoms, a benzyl group, or a 3,4-methylenedioxybenzyl group.
Examples of the acyl group having 2 to 4 carbon atoms are acetyl, propionyl, butyroyl and isobutyroyl groups.
Examples of the alkoxycarbonyl group having 2 to 5 carbon atoms are methoxycarbonyl and ethoxycarbonyl groups.
Examples of the alkoxycarbonylmethyl group having 3 to 5 carbon atoms are methoxycarbonylmethyl and ethoxycarbonylmethyl groups.
In formula (I), R.sup.2 represents a hydrogen atom, an amino group, a monoalkylamino group having 1 to 4 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, or an alkoxycarbonyl group having 2 to 4 carbon atoms.
Examples of the monoalkylamino group having 1 to 4 carbon atoms are methylamino, ethylamino, propylamino, isopropylamino and sec-butylamino groups.
Examples of the alkoxy group having 1 to 5 carbon atoms are methoxy, ethoxy, propoxy, iso-propoxy, butoxy, sec-butoxy, iso-butoxy and tert-butoxy groups.
Examples of the alkoxycarbonyl groups having 2 to 4 carbon atoms may be the same as those given above for R.sup.1.
In formula (I), R.sup.3 represents a hydrogen atom, an alkoxycarbonyl group having 2 to 4 carbon atoms, a dialkylaminocarbonyl group having 1 to 9 carbon atoms in each alkyl moiety, an alkoxy group having 1 to 5 carbon atoms, or a hydroxyethyl group.
Examples of the alkoxycarbonyl group having 2 to 4 carbon atoms may be the same as those given hereinabove with regard to R.sup.1.
Examples of the dialkylaminocarbonyl groups having 1 to 9 carbon atoms in each alkyl moiety are dimethylaminocarbonyl, diethylaminocarbonyl, diisopropylaminocarbonyl and dibutylaminocarbonyl groups.
Examples of the alkoxy group having 1 to 5 carbon atoms may be the same as those given hereinabove in regard to R.sup.2.
In formula (I), R.sup.2 and R.sup.3 may form a 4- to 7-membered carbocyclic ring or a heterocyclic ring having N, O or S as the hetero atom together with the carbon atoms to which they are bonded.
Examples of a group formed by R.sup.2 and R.sup.3 together are shown below. ##STR8##
wherein l.sub.1 is a number of 2, 3 or 4. ##STR9##
wherein X is .dbd.O or .dbd.N--R.sup.5 in which R.sup.5 represents a hydroxyl, benzylsulfonyloxy or toluenesulfonyloxy group, and l.sub.2 represents a number of 2, 3, or 4. ##STR10##
wherein R.sup.6 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or an alkoxy alkyl group resulting from substitution of an alkyl group having 2 to 4 carbon atoms by an alkoxy group having 1 to 4 carbon atoms, R.sup.7 and R.sup.8 are identical or different and each represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, l.sub.3 is 2 and l.sub.4 is 0, or l.sub.3 is 0 and l.sub.4 is 1. ##STR11##
wherein R.sup.9 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and l.sub.5 is a number of 2 or 3. ##STR12##
wherein R.sup.10 represents a hydrogen atoms, an alkyl group having 1 to 10 carbon atoms, an acyl group having 1 to 4 carbon atoms, or a carbamoylmethyl group, and l.sub.6 is a number of 1 or 2. ##STR13##
wherein R.sup.11 represents a hydrogen atom, a formyl group, an alkyl group having 1 to 4 carbon atoms, or an aralkyl group having 7 to 9 carbon atoms, and R.sup.12 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 3 to 4 carbon atoms, a hydroxyalkyl group having 2 to 4 carbon atoms, an alkoxyalkyl group resulting from substitution of an alkyl group having 2 to 4 carbon atoms by an alkoxy group having 1 to 4 carbon atoms, a benzyl group, or a cycloalkyl group having 3 to 6 carbon atoms, ##STR14##
wherein R.sup.13 and R.sup.14 are identical or different, and each represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and l.sub.7 is a number of 0, 2 or 3, EQU --E--G-- (h)
wherein E--G is --OCH.sub.2 CH.sub.2 --, --OC(CH.sub.3).dbd.CH--, --CH.sub.2 OCO--, --OCOCH.sub.2 --, --CH.sub.2 C(CH.sub.3)OCO--, --N(CH.sub.3)CH.sub.2 CH.sub.2 --, --CH.dbd.CH--CH.dbd.CH--, --CH.dbd.C(OCH.sub.3)--C(OCH.sub.3).dbd.CH--, or ##STR15##
Examples of the alkyl group having 1 to 4 carbon atoms for R.sup.6 in (c) above are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, iso-butyl and tert-butyl.
Examples of the alkoxyalkyl group for R.sup.6 resulting from substitution of an alkyl group having 2 to 4 carbon atoms by an alkoxy group having 1 to 4 carbon atoms are methoxyethyl, ethoxyethyl, propoxyethyl, butoxyethyl, methoxypropyl and methoxybutyl.
Examples of the alkyl group having 1 to 4 carbon atoms for R.sup.7 and R.sup.8 are the same as those given hereinabove with regard to R.sup.6.
Examples of the alkyl group having 1 to 4 carbon atoms for R.sup.9 in (d) are the same as those given above with regard to R.sup.6.
Examples of the alkyl group having 1 to 10 carbon atoms for R.sup.10 in (e) above are methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, nonyl and decyl groups.
Examples of the acyl group having 1 to 4 carbon atoms for R.sup.10 are formyl, acetyl, propionyl and butyroyl groups.
Examples of the alkyl group having 1 to 4 carbon atoms for R.sup.11 in (f) are the same as those given above with regard to R.sup.6.
Examples of the aralkyl group having 7 to 9 carbon atoms for R.sup.11 are benzyl, 4-methylbenzyl, 4-methoxybenzyl, 4-nitrobenzyl, 2-phenylethyl and 3-phenylethyl groups.
Examples of the alkyl group having 1 to 4 carbon atoms for R.sup.12 are the same as those given above with regard to R.sup.6.
Examples of the alkenyl group having 3 to 4 carbon atoms for R.sup.12 are allyl, 4-methylallyl and 3-methylallyl groups.
Examples of the hydroxyalkyl group having 2 to 4 carbon atoms for R.sub.12 are 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 2-hydroxypropyl and 2-hydroxybutyl groups.
Examples of the alkoxyalkyl group resulting from substitution of an alkyl group having 2 to 4 carbon atoms by an alkoxy group having 1 to 4 carbon atoms may be the same as those given hereinabove with regard to R.sup.6.
Examples of the alkyl group having 1 to 4 carbon atoms for R.sup.13 and R.sup.14 in (g) above may be the same as those given above with regard to R.sup.6.
In formula (I), examples of the alkyl group having 1 to 4 carbon atoms for R.sup.4 may be the same as those given above with regard to R.sup.6.
Examples of the alkylthio group having 1 to 4 carbon atoms for R.sup.4 are methylthio, ethylthio, propylthio, butylthio, isopropylthio, and sec-butylthio groups.
Specific examples of the compounds of formula (I) as the active ingredient of the therapeutic agent of this invention for neurological diseases are exemplified below in some groups divided according to the definitions of R.sup.2 and R.sup.3 for the sake of convenience.
Compounds in which R.sup.2 and R.sup.3 are not bonded to each other:
__________________________________________________________________________ (100) ##STR16## m.p. 78-79.degree. C. (102) ##STR17## (104) Maleate of (102) (106) ##STR18## (108) Maleate of (106) (110) ##STR19## (112) Maleate of (110) (114) ##STR20## (116) Maleate of (114) (118) ##STR21## (120) Maleate of (118) (122) ##STR22## (124) Maleate of (122) (126) ##STR23## (128) Maleate of (126) (130) ##STR24## (132) Maleate of (130) (134) ##STR25## (136) Maleate of (134) (138) ##STR26## m.p. 195-197.degree. C. (140) 2-Naphthalenesulfonate of (140) m.p. 215-217.degree. C. (142) ##STR27## (144) Hydrochloride of (142) Compounds of the following formula (I)-a ##STR28## (I)-a wherein R.sup.1, and R.sup.4 and l.sub.1 are as defined above, and R.sup.2 and R.sup.3 are bonded to each other to form the group ( CH .sub.2 ) .sub.l.sbsb.1. (200) ##STR29## m.p. 107-113.degree. C. (202) Hydrochloride of (200) m.p. above 300.degree. C. (204) ##STR30## (206) Maleate of (204) m.p. 165-167.degree. C. (208) ##STR31## m.p. 90-95.degree. C. Compounds of the following formula (I)-b ##STR32## (I)-b wherein R.sup.1, R.sup.4, X and l.sub.2 are as defined above, and R.sup.2 and R.sup.3 are bonded to each other to form the ##STR33## (300) ##STR34## (302) Hydrochloride of (300) m.p. 288-290.degree. C. (decomp.) (304) ##STR35## (306) ##STR36## (308) ##STR37## Compounds of the following formula (I)-c ##STR38## (I)-c wherein R.sup.1, R.sup.4, R.sup.6, R.sup.7, R.sup.8, l.sub.3 and l.sub.4 are as defined above, and R.sup.2 and R.sup.3 are bonded to each ##STR39## (400) ##STR40## (402) ##STR41## (404) ##STR42## (406) Hydrochloride of (404) m.p. above 300.degree. C. (408) Maleate of (404) m.p. 179-182.degree. C. (410) Oleate of (404) m.p. 254-256.degree. C. (412) p-Toluenesulfonate of (404) m.p. 224-225.degree. C. (414) Citrate of (404) m.p. 187-188.degree. C. (416) Tortrate of (404) m.p. 230-232.degree. C. (decomp.) (418) Phosphate of (404) m.p. 286-289.degree. C. (decomp.) (420) 2-Naphthalenesulfonate of (404) m.p. 282-283.degree. C. (decomp.) (422) ##STR43## (424) Hydrochloride of (422) m.p. above 300.degree. C. (426) ##STR44## (428) Hydrochloride of (426) m.p. 257-259.degree. C. (430) Maleate of (426) m.p. 158-160.degree. C. (432) ##STR45## (434) 2-Naphthalenesulfonate of (432) m.p. 74-82.degree. C. (436) ##STR46## m.p. 122-124.degree. C. (438) 2-Naphthalenesulfonate of (436) m.p. 234-239.degree. C. (decomp.) (440) ##STR47## m.p. 194-195.degree. C. (442) ##STR48## m.p. 170-171.degree. C. (444) ##STR49## m.p. 167.2-169.2.degree. C. (446) Maleate of (444) m.p. 181-183.degree. C. (448) ##STR50## m.p. 113-116.degree. C. (450) 2-Naphthalenesulfonate of (448) m.p. 211-212.degree. C. (452) ##STR51## (454) Hydrochloride of (452) m.p. above 300.degree. C. (456) ##STR52## m.p. 142-146.degree. C. (458) ##STR53## m.p. 76-79.degree. C. (460) ##STR54## (462) ##STR55## (464) ##STR56## (466) Hydrochloride of (464) m.p. above 300.degree. C. (468) Maleate of (464) m.p. 181-183.degree. C. (decomp.) Compounds of the following formula (I)-d ##STR57## (I)-d wherein R.sup.1, R.sup.4, R.sup.9 and l.sub.5 are as defined as above, and R.sup.2 and R.sup.3 are bonded to each other to form ##STR58## (500) ##STR59## (502) Hydrochloride of (500) (504) ##STR60## (506) ##STR61## Compounds of the following formula (I)-e ##STR62## (I)-e wherein R.sup.1, R.sup.4, R.sup.10 and l.sub.6 are as defined above, and R.sup.2 and R.sup.3 are bonded to each other to form ##STR63## (600) ##STR64## m.p. 182-183.degree. C. (602) Hydrochloride of (600) m.p. above 300.degree. C. (604) Maleate of (600) m.p. 193-195.degree. C. (606) Phosphate of (600) m.p. above 300.degree. C. (608) Naphthalenssulfonate of (600) m.p. 272-273.degree. C. (610) ##STR65## (612) Hydrochloride of (610) m.p. 245-250.degree. C. (614) ##STR66## (616) Hydrochloride of (614) m.p. above 300.degree. C. (618) ##STR67## (620) Hydrochloride of (618) m.p. above 300.degree. C. (622) ##STR68## (624) Hydrochloride of (622) m.p. 250-255.degree. C. (decomp.) (626) ##STR69## (628) Hydrochloride of (626) m.p. 275-280.degree. C. (630) ##STR70## (632) ##STR71## (634) ##STR72## (636) ##STR73## m.p. 110-115.degree. C. (638) Maleate of (636) m.p. 151-152.degree. C. (640) ##STR74## m.p. 162-164.degree. C. (642) Maleate of (640) m.p. 202-203.degree. C. (644) ##STR75## m.p. 106-112.degree. C. (646) Maleate of (644) m.p. 134-136.degree. C. (648) ##STR76## (650) 2-Naphthalenesulfonate of (648) m.p. 260-263.degree. C. (decomp.) (652) ##STR77## m.p. 239-241.degree. C. (decomp.) (654) 2-Naphthalenesulfonate of (652) m.p. 276-277.degree. C. (decomp.) (656) ##STR78## m.p. 131-134.degree. C. (658) ##STR79## m.p. 132- 134.degree. C. (660) ##STR80## m.p. 179-182.degree. C. (662) ##STR81## m.p. 145-147.degree. C. (664) ##STR82## m.p. 176-178.degree. C. (666) ##STR83## m.p. 229-232.degree. C. (decomp.) (668) ##STR84## m.p. 152-154.degree. C. (670) 2-Naphthalenesulfonate of (668) m.p. 180-184.degree. C. (672) ##STR85## (674) 2-Naphthalenesulfonate of (672) m.p. 70-77.degree. C. (676) ##STR86## m.p. 158-163.degree. C. (678) 2-Naphthalenesulfonate of (676) m.p. 236-237.degree. C. (decomp.) (680) ##STR87## m.p. 129-132.degree. C. (682) ##STR88## (684) ##STR89## m.p. 174-177.degree. C. Compounds of the following formula (I)-f ##STR90## (I)-f wherein R.sup.1, R.sup.4, R.sup.11 and R.sup.12 are as defined above, and R.sup.2 and R.sup.3 are bonded to each other to form ##STR91## (700) ##STR92## m.p. 252.8.degree. C. (701) Hydrochloride of (700) (702) ##STR93## (704) ##STR94## (706) ##STR95## Oil (707) Hydrochloride of (706) (708) ##STR96## m.p. 149-152.degree. C. (710) Hydrochloride of (708) m.p. 227-279.degree. C. (712) ##STR97## m.p. 161.degree. C. (713) Hydrochloride of (712) (714) ##STR98## m.p. 143.degree. C. (715) Hydrochloride of (714) (716) ##STR99## (718) ##STR100## (720) ##STR101## (722) ##STR102## (724) ##STR103## (726) ##STR104## (728) ##STR105## (730) ##STR106## (732) ##STR107## (734) ##STR108## m.p. 170-172.degree. C. (736) ##STR109## (738) ##STR110## (740) ##STR111## m.p. 231.7.degree. C. (742) ##STR112## m.p. above 300.degree. C. (744) Hydrochloride of (742) m.p. above 300.degree. C. (746) ##STR113## (748) Hydrochloride of (746) Compounds of the following formula (I)-g ##STR114## (I)-g wherein R.sup.1, R.sup.4, R.sup.13, R.sup.14 and l.sub.7 are as defined above, and R.sup.2 and R.sup.3 are bonded to each other to ##STR115## (800) ##STR116## (802) Hydrochloride of (800) (804) ##STR117## (806) ##STR118## Compounds of the following formula (I)-h ##STR119## (I)-h wherein R.sup.1, R.sup.4 and E-G are as defined above, and R.sup.2 and R.sup.3 are bonded to each other to form the group E-G (900) ##STR120## m.p. 74-78.degree. C. (902) Hydrochloride of (900) m.p. 294.degree. C. (decomp.) (904) ##STR121## m.p. above 300.degree. C. (906) Hydrochloride of (904) m.p. above 300.degree. C. (908) ##STR122## m.p. 159-160.degree. C. (910) Maleate of (908) m.p. 183-185.degree. C. (912) ##STR123## m.p. 63-65.degree. C. (914) 2-Naphthalenesulfonate of (912) m.p. 160-162.degree. C. (916) ##STR124## (918) Hydrochloride of (916) m.p. 274-276.degree. C. (decomp.) (920) ##STR125## (922) p-Toluenesulfonate of (920) m.p. 214-218.degree. C. (decomp.) (924) ##STR126## (926) ##STR127## m.p. 121-123.degree. C. (928) ##STR128## m.p. 121-123.degree. C. (930) ##STR129## m.p. 105-107.degree. C. (932) ##STR130## (934) ##STR131## (936) Maleate of (934) (938) ##STR132## (940) Hydrochloride of (938) (942) ##STR133## (944) ##STR134## m.p. 188-190.degree. C. __________________________________________________________________________
The compound of formula (I) used as the active ingredient in this invention can be produced by a method known per se, particularly by the methods described in Japanese Laid-Open Patent Publications Nos. 140568/1986, 87627/1986 and 1040568/1986 and by treating the intermediates obtained by these methods known per se (for example, reductive elimination of the protective group). Examples 1A to 48A below describe the production of the compounds in detail.
The compound of formula (I) is usually used in the form of a pharmaceutical composition, and administered through various routes, for example, oral, subcutaneous, intramuscular, intravenous, intrarhinal, skin permeation or intrarectal.
The present invention includes a pharamceutical preparation comprising a pharmaceutically acceptable carrier and the compound of general formula (I) or its pharmaceutically acceptable salt as an active ingredient. The pharmaceutically acceptable salt includes acid addition salts or quaternary ammonium (or amine) salts.
Examples of the pharmaceutically acceptacle salts of the compound (I) include hydrochlorides, hydrobromides, sulfates, bisulfites, phosphates, acidic phosphates, acetates, maleates, fumarates, succinates, lactates, tartrates, benzoates, citrates, gluconates, glucanates, methanesulfonates, p-toluenesulfonates and naphthalenesulfonates which are formed from acids capable of forming pharmaceutically acceptable anion-containing nontoxic acid addition salts, hydrates thereof, and quaternary ammonium (or amine) salts or hydrates thereof. The composition of this invention may be formulated into tablets, capsules, powders, granules, troches, cachet wafer capsules, elixirs, emulsions, solutions, syrups, suspensions, aerosols, ointments, aseptic injectables, molded cataplasmas, tapes, soft and hard gelatin capsules, suppositories, and aseptic packed powders. Examples of the pharmaceutically acceptable carrier include lactose, glucose, sucrose, sorbitol, mannitol, corn starch, crystalline cellulose, gum arabic, calcium phosphate, alginates, calcium silicate, microcrystalline cellulose, polyvinyl pyrrolidone, tragacanth gum, gelatin, syrup, methyl cellulose, carboxymethyl cellulose, methylhydroxybenzoic acid esters, propylhydroxybenzoic acid esters, talc, magnesium stearates, inert polymers, water and mineral oils.
Both solid and liquid compositions may contain the aforesaid fillers, binders, lubricants, wetting agents, disintegrants, emulsifying agents, suspending agents, preservatives, sweetening agents and flavoring agents. The composition of this invention may be formulated such that after administration to a patient, the active compound is released rapidly, continuously or slowly.
In the case of oral administration, the compound of formula (I) is mixed with a carrier or diluent and formed into tablets, capsules, etc. In the case of parenteral administration, the active ingredient is dissolved in a 10% aqueous solution of glucose, isotonic salt water, sterilized water or a like liquid, and enclosed in vials or ampoules for intravenous installation or injection or intramuscular injection. Advantageously, a dissolution aid, a local anesthetic agent, a preservative and a buffer may also be included into the medium. To increase stability, it is possible to lyophilize the present composition after introduction into a vial or ampoule. Another example of parenteral administration is the administration of the pharmaceutical composition through the skin as an ointment or a cataplasm. In this case, a molded cataplasm or a tape is advantageous.
The composition of this invention contains 0.1 to 2000 mg, more generally 0.5 to 1000 mg, of the active component for each unit dosage form.
The compound of formula (I) is effective over a wide dosage range. For example, the amount of the compound administered for one day usually falls within the range of 0.003 mg/kg to 100 mg/kg. The amount of the compound to be actually administered is determined by a physician depending, for example, upon the type of the compound administered, and the age, body weight, reaction, condition, etc. of the patient and the administration route.
The above dosage range, therefore, does not limit the scope of the invention. The suitable number of administrations is 1 to 6, usually 1 to 4, daily.
The compound of formula (I) by itself is an effective therapeutic agent for disorders of the peripheral nervous system and the central nervous system. If required, it may be administered in combination with at least one other equally effective drug. Examples of such an additional drug are gangliosides, mecobalamin and isaxonine.
The formulation of the compounds of formula (I) used in this invention and their biological activities will now be illustrated in more detail by a series of Examples B and C below. These examples, however, do not limit the present invention. The following examples of a composition use one of the compounds described in the specification or another therapeutic compound within the general formula (I) as an active ingredient.